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Published on: July 21, 2018

Loss of integrin alpha1beta1 ameliorates Kras-induced lung cancer

Ines Macias-Perez1, Corina Borza, Xiwu Chen

  • 1Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Veterans Affairs Hospital, Nashville, Tennessee 37232, USA.

Cancer Research
|August 5, 2008
PubMed

Insights

Integrin alpha1beta1 promotes non-small cell lung cancer growth. Loss of integrin alpha1 reduces lung tumor incidence and progression in Kras-driven mouse models, indicating a cooperative role in cancer development.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Integrin alpha1beta1, a collagen IV binding receptor, is implicated in lung cancer via proangiogenic effects.
  • Its direct role in primary lung tumor promotion remains largely uncharacterized.

Purpose of the Study:

  • To investigate the direct role of integrin alpha1beta1 in promoting primary lung tumors initiated by oncogenic Kras.
  • To elucidate the molecular mechanisms underlying integrin alpha1's function in non-small cell lung cancer (NSCLC) development.

Main Methods:

  • Crossed integrin alpha1-null mice with KrasLA2 mice (carrying oncogenic Kras G12D mutation) to generate KrasLA2/alpha1-null and control littermates.
  • Assessed tumor incidence, survival, vascularization, proliferation (PCNA), apoptosis (TUNEL), and kinase activation (ERK, p38 MAPK).
  • Evaluated anchorage-independent colony formation, collagen-mediated proliferation, ERK activation, and tumorigenicity of isolated tumor cells in vivo.

Main Results:

  • KrasLA2/alpha1-null mice exhibited decreased primary lung tumor incidence and prolonged survival compared to controls.
  • Tumors in KrasLA2/alpha1-null mice were smaller, less vascularized, with reduced proliferation and increased apoptosis.
  • Loss of integrin alpha1 diminished ERK activation but enhanced p38 MAPK activation, and reduced tumor cell tumorigenicity and proliferation.

Conclusions:

  • Loss of the integrin alpha1 subunit significantly decreases the incidence and growth of lung epithelial tumors initiated by oncogenic Kras.
  • Integrin alpha1beta1 and oncogenic Kras cooperate to drive the progression of non-small cell lung cancer in vivo.
  • Targeting integrin alpha1beta1 may represent a therapeutic strategy for NSCLC.

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